Enhanced delivery of 5-iodo-2'-deoxyuridine to the brain parenchyma.

Abstract:

:5'-Ester derivatives of 5-iodo-2'-deoxyuridine (IDU) with varying degrees of lipophilicity were examined to evaluate the effectiveness of lipophilic ester prodrugs for enhanced and sustained delivery of IDU to the brain parenchyma. Approximately 1.0% (1.0 +/- 0.19; n = 4) of the total radioactivity was found in the brain at 30 min following intravenous administration of the lipophilic benzoyl-5'-ester of 125I-labeled IDU, whereas IDU per se yielded only 0.01% (0.01 +/- 0.06; n = 4). Since the IDU 5'-esters generated significantly higher levels of IDU in the brain, an HPLC analysis of IDU in the presence of 5'-esters and the metabolite 5-iodouracil was developed to characterize IDU uptake in the brain. The drug was detected at levels of 6.6 and 9.5 micrograms/g of brain tissue at 3 hr following intravenous administration of valeryl and benzoyl IDU, respectively, at a dose level of 40 mg/kg IDU equivalent each. IDU, on the other hand, when injected at a similar dose level, produced concentration levels below 0.01 micrograms/g of brain tissue, which was too low to be detected accurately by the HPLC assay. These results suggest that the 5'-ester derivatives cross the blood-brain barrier effectively and generate significantly higher brain levels of the parent drug in the brain parenchyma. The regenerated hydrophilic drug because of its polarity is "locked in" the brain and is subsequently metabolized by pyrimidine phosphorylase to 5-iodouracil.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Ghosh MK,Mitra AK

doi

10.1023/a:1015803922401

subject

Has Abstract

pub_date

1992-09-01 00:00:00

pages

1173-6

issue

9

eissn

0724-8741

issn

1573-904X

journal_volume

9

pub_type

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